The adaptive response (AR) is a phenomenon whereby the harmful effects of high dose ionizing radiation or other genotoxic agents can be mitigated by prior exposure to a low dose of the same or similar genotoxic stress. The adapted cells show an increased survival, less chromosomal aberration and decreased mutagenesis termed the adaptive response. It is not clear which biologic pathways are involved in the AR, speculation centers on cell cycle controls, signal transduction, and DNA repair mechanisms. DNA repair mechanisms, once thought to be constitutive, have now been proven to be inducible. Wilson, Mitra, and others have shown that genes and gene products involved in base excision repair are induced after low doses of certain forms of DNA damaging agents. We are working on the hypothesis that induced DNA repair, both base excision and nucleotide excision repair are equally important as underlying mechanisms of AR. The components of the proximal limb of the p53 DNA damage response pathway likely are critical in the initiation and maintenance of the adaptive response. We believe that the most interesting hypotheses to construct center on understanding the role of p53 damage response pathways in the adaptive response. Specifically, we hypothesize that nucleotide excision repair induced by low doses of ionizing radiation occurs through induction or activation of p53 related genes. There is evidence that PARP and ATM are required for AR. However, the role of DNA-PK in concert with these two components and possible c-ABL is unclear. It is also not discerned how other p53 related genes such as interferon regulatory factors 1 and 2 (IRF1,2), GADD45, p21 are involved. GADD45 known to be induced by low-moderate doses of ionizing radiation and IRF 1 a tumor suppresser protein and transcription factor known to regulate responses to DNA damage by interacting with p53 and p21 have yet to be examined in the AR pathway. We speculate that these genes are critical elements in the AR because they are essential in the DNA damage recognition mechanisms, and cell cycle check points and may activate or induce nucleotide excision repair. Although Human AP Endonuclease 1 has been implicated as a possible gene involved in the induction of base excision repair after low doses of oxidative damage, it is not known which nucleotide excision repair related genes may play a comparable role. Our work to date has focused on evaluating the role of DNA-PK in AR. Using SCID mouse models with different mutations in DNA-PK, we are evaluating AR in terms of biological endpoints that include apoptosis, cell survival, and persistence of DNA damage measured by the Single Cell Gel Electrophoresis (COMET Assay) after gamma irradiation. Other mutant cell lines with defects in p53 related genes and nucleotide excision repair related genes will be used as well to dissect the pathways involved. We will also quantify the magnitude of nucleotide excision repair induced by low doses of ionizing radiation.